Detailed characterization of experimentally derived human hepatic CYP1A1 activity and expression using differential inhibition of ethoxyresorufin O-deethylation by fluvoxamine

Objective: To characterize the distribution of mathematically derived human hepatic CYP1A1 activity using differential inhibition of ethoxyresorufin O -deethylation (EROD) by fluvoxamine. Methods: Quantitative CYP1A1- and CYP1A2-mediated EROD activities were dete rmined in 42 human livers using differential inhibition of EROD by fluvoxam ine. CYP1A2-specific activity was also measured by phenacetin O-deethylatio n and caffeine 3-demethylation. Distributions of CYP1A1-mediated EROD and C YP1A2 probe activities were analyzed using cumulative distribution (probit) plots and the Kolgomorov-Smirnov test. Age effect on CYP1A1- and CYP1A2-me diated EROD activities was evaluated using descriptive statistics and analy sis of variance. Results: The derived CYP1A1 protein concentration of 0.58 +/- 1.04 pmol/mg was only 4% of the derived CYP1A2. Since CYP1A1 is intrinsically far more a ctive than CYP1A2 in mediating EROD, contribution of CYP1A1 to EROD represe nted approximately 25-40% of CYP1A2 contribution. Three of the 42 livers ex hibited no CYP1A1-mediated EROD. Approximately 8% of the individuals showed high CYP1A1 activity phenotype based on cumulative distribution curve anal ysis. Hepatic CYP1A1 activity was more variable than that of CYP1A2. The va riance of CYP1A1-mediated EROD was significantly different from that of CYP 1A2, using the Kolgomorov-Smirnov statistical test. Even though not statist ically significant, an age-related pattern in CYP1A1-mediated activity was identified: activity was high in the pre-puberty group, then decreased in t he young/mature adult group and, finally, a slight increase was observed in old age. Conclusions: Distribution pattern in CYP1A1-mediated EROD suggests that the low derived CYP1A1 expression is most likely induced rather than constitut ive. CYP1A1 activity deviates from log-normal distribution; the variations in hepatic CYP1A1 activity may affect the conversion of procarcinogens to c arcinogens. The age-related trend in CYP1A1-mediated EROD activity hints th at CYP1A1 responsiveness to inducers may change with age as well as with ex posure to environmental inducers. These findings prompt (1) future genotypi ng studies to determine whether increased CYP1A1 inducibility is a result o f genetic factors and (2) studies to address whether CYP1A1 inducibility ch anges with age.